1. Introduction
[0001] Cancer is a significant health problem in the world. Although advances have been
made in cancer detection and treatment, no vaccine or other universally successful
preventive or therapeutic method is currently available. Management of the disease
currently relies on a combination of early diagnosis and aggressive treatment, which
may include one or more of a variety of therapies such as surgery, radiotherapy, chemotherapy
and hormone therapy. While such therapies provide benefit to many patients, a high
mortality continues to be observed for many cancers. The development of improved anti-tumour
agents would facilitate cancer prevention and treatment.
[0002] Unfortunately, cancer is the leading cause of death, second only to heart disease,
of both men and women. In the fight against cancer, numerous techniques have been
developed and are the subject of current research directed to understanding the nature
and cause of the disease and to providing methods for the control or cure thereof.
[0003] Although thousands of potential anti-cancer agents have been evaluated, the treatment
of human cancer remains fraught with complications, which often present an array of
suboptimal treatment choices. As such, chemotherapeutic agents, which possess little
or no toxicity, which are inexpensive to obtain or manufacture, which are well tolerated
by the patient, and which are easily administered would be a desirable addition to
the therapeutic modalities currently available to the oncologist. Agents that will
selectively sensitise malignant tissue to allow lower doses of radiation or therapy
to achieve the same therapeutic effect with less damage to healthy tissues are also
desirable. Similarly, agents that prevent cancer from occurring or reoccurring are
also desirable. The present invention remedies these needs by providing such chemotherapeutic
and sensitising agents.
[0004] Therefore, the technical problem underlying the present invention is to provide alternative
or further compounds with anti-cancer activity and methods for the clinical use.
[0005] This problem is solved by the provision of the embodiments as defined in the claims.
[0006] The compounds of this invention are useful in treating cancer. They are effective
in inhibiting survival and/or growth of cancer cells and/or for inhibiting undesirable
cell growth in general.
[0007] This invention further provides pharmaceutical and therapeutic compositions which
contain a pharmaceutically or therapeutically effective amount of these compounds
[0008] The role of arsenic trioxide in the treatment of cancer as described by several inventors
is different from this invention, whereas the role of arsenic (
WO 800245; Komipharm International) for the treatment of malignancies was limited to primary
tumours.
[0009] Also disclosed is a kit for inhibiting abnormal cell growth comprising of arsenous
acid sodium salt.
[0010] As used herein, including the appended claims, singular forms of words such as "a,"
"an," and "the" include their corresponding plural referents unless the context clearly
dictates otherwise. Thus, e.g., reference to "an organism" includes one or more different
organisms, reference to "a cell" includes one or more of such cells, and reference
to "a method" includes reference to equivalent steps and methods known to a person
of ordinary skill in the art, and so forth.
[0011] Unless otherwise defined, all technical and scientific terms used herein have the
same meaning as commonly understood by a person of ordinary skill in the art to which
this invention belongs. Although methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the present invention,
suitable methods and materials are described below.
[0012] Prior to setting forth the invention it may be helpful to an understanding thereof
to set forth definitions of certain terms to be used hereinafter.
[0013] A "patient" for the purposes of the present invention includes humans and other animals,
particularly mammals, and other organisms. Thus the methods are applicable to both
human therapy and veterinary applications. In the preferred embodiment the patient
is a mammal, and in the most preferred embodiment the patient is human.
[0014] The term "animal" refers to an organism with a closed circulatory system of blood
vessels and includes birds, mammals and crocodiles. The term "animal" used here also
includes human subjects.
[0015] The term "angiogenesis" refers to the generation of new blood vessels into cells,
tissue, organs or tumours.
[0016] The term "metastasis" refers to the process by which tumour cells are spread to distant
parts of the body. The term is also used herein to refer to a tumour that develops
through the metastatic process.
[0017] The term "contacting" is used herein interchangeably with the following: combined
with, added to, mixed with, passed over, incubated with, flowed over, etc. Moreover,
the compounds of present invention can be "administered" by any conventional method
such as, for example, parenteral, oral, and topical and inhalation routes as described
herein.
[0018] As used herein, the term "safe and effective amount" refers to the quantity of a
component that is sufficient to yield a desired therapeutic response without undue
adverse side effects (such as toxicity, irritation, or allergic response) commensurate
with a reasonable benefit/risk ratio when used in the manner of this invention. What
is meant by a "therapeutically effective amount" is an amount of a compound of the
present invention effective to yield the desired therapeutic response. This amount
for example could be effective in delaying the growth, delaying metastasis inhibiting
angiogenesis and/or tolemere and/or causing shrinkage of cancer, either a sarcoma
or lymphoma. The specific safe and effective amount or therapeutically effective amount
will vary with such factors as the particular condition being treated, the physical
condition of the patient, the type of mammal being treated, the duration of the treatment,
the nature of concurrent therapy (if any), and the specific formulations employed
and the structure of the compounds or its derivatives.
[0019] "An anti-angiogenic" amount refer to an amount of a compound or composition effective
to depress, suppress or inhibit angiogenesis or result in amelioration of symptoms
associated with an angiogenic disease. The desired result can be either a subjective
relief of a symptom(s) or an objectively identifiable improvement in the recipient
of the dosage, a decrease in the vascularisation of endothelial cells or a decrease
in the rate of angiogenesis as noted by a clinician or other qualified observer.
[0020] The terms "treating cancer," "therapy," and the like refer generally to any improvement
in the mammal having the cancer wherein the improvement can be ascribed to treatment
with the compounds of the present invention. The improvement can be either subjective
or objective. For example, if the mammal is human, the patient may note improved vigour
or vitality or decreased pain as subjective symptoms of improvement or response to
therapy. Alternatively, the clinician may notice decrease in tumour size or tumour
burden based on physical exam, laboratory parameters, tumour markers or radiographic
findings. Some laboratory signs that the clinician may observe for response to therapy
include normalization of tests such as white blood cell count, red blood cell count,
platelet count, erythrocyte sedimentation rate, and various enzyme levels. Additionally,
the clinician may observe a decrease in a detectable tumour marker. Alternatively,
other tests can be used to evaluate objective improvement such as sonograms, nuclear
magnetic resonance testing and positron emissions testing.
[0021] "Inhibiting the growth of tumour cells" can be evaluated by any accepted method of
measuring whether growth of the tumour cells has been slowed or diminished. This includes
direct observation and indirect evaluation such as subjective symptoms or objective
signs as discussed above.
[0022] Accordingly, the compositions of the invention are administered to cells. By "administered"
herein is meant administration of a therapeutically effective dose of the candidate
agents of the invention to a cell either in cell culture or in a patient. By "therapeutically
effective dose" herein is meant a dose that produces the effects for which it is administered.
The exact dose will depend on the purpose of the treatment, and will be ascertainable
by one skilled in the art using known techniques. As is known in the art, adjustments
for systemic versus localized delivery, age, body weight, general health, sex, diet,
time of administration, drug interaction and the severity of the condition may be
necessary, and will be ascertainable with routine experimentation by those skilled
in the art. By "cells" herein is meant almost any cell in which mitosis or meiosis
can be altered.
[0023] Therefore, the present invention related to a pharmaceutical anti-cancer composition
comprising a therapeutically effective amount of arsenous acid sodium salt represented
by the following formula (I) :
2. Field of invention
[0024] The present invention relates to compounds and compositions for the treatment of
metastatic neoplastic diseases, including, but not limited to urogenital carcinomas.
[0025] More specifically, the present invention relates to novel chemotherapeutic compositions
of arsenous acid sodium salt metastatic tumours of the urogenital system; and bladder,
kidney, testicular and metastatic bone cancer.
3. Background to the Invention
[0026] The majority of chemotherapeutic drugs are currently developed for intravenous use.
Oral treatment with anti-cancer agents, however, is now of interest due to the benefits
of easy administration, better patient compliance and the reduction in cost and the
increase in the quality of life of the patients. For example, patients will be able
to undergo oral treatment as outpatients.
[0027] Therefore, it is clear that oral drugs for cancer treatment have a future and will
play a more important role than they have done in the past. Patient's preferences
and quality of life issues, which are becoming central considerations in palliative
treatment regimens, precede the development of orally administered drugs. Intravenous
(iv) administration is a major source of discomfort and stress for cancer patients
and approximately 90 % of patients asked, express a preference for oral versus iv
chemotherapy, predominantly because of the convenience of administration outside a
clinical setting or current concerns about previous problems with intravenous access.
[0028] One of the key objectives of the present invention to provide a chemotherapeutic
product for the treatment of cancer and which exhibits high bioavailability, enhanced
anti-cancer activity and high level of safety following oral administration.
3.1 Urogenital Cancer
[0029] Genitourinary malignancies are composed of (amongst others) cancers of the prostate,
bladder, kidney, and testis. The challenges presented by these malignancies parallel
those confronting investigators and practicing cliniciana in treating all other types
of cancers. Smoking, which is strongly associated with the development of lung cancer,
is responsible for one third of bladder cancers, and several studies implicate obesity
with an increased risk for colon, breast, and kidney cancers.
3.2 Bladder Cancer
[0030] Carcinomas of the urinary tract occur in 90% of the cases directly in the bladder,
8% in the renal pelvis and 2% in the ureter or urethra. Bladder cancer is the fourth
most common cancer in men and the eighth in women. Estimates are that 25% of the bladder
cancers in men are related to occupational exposure and 50% to cigarette smoking.
Smoking is a key determining risk, which persists for up to 10 years after smoking
cessation. The choice of treatment is based on disease extent: superficial, invasive
or metastatic. Combination chemotherapy is used to treat metastatic disease. Urothelial
tumours are chemosensitive, and a number of single agents result in short-term regressions
in 20 to 30 percent of cases. One regimen is called the MVAC regimen. It consists
of combination treatment with methotrexate, vinblastine, adriamycin (doxorubicin)
and cisplatin. Several drugs are given over a few days with the drugs then being repeated
every few weeks for several months.
3.3 Renal Cancer
[0031] Renal cell carcinoma accounts for 90 to 95 percent of malignant neoplasm's arising
from the kidney. Renal cell carcinoma affects more than 30,000 American annually and
is responsible for nearly 12,000 deaths in the United States each year. Renal cell
carcinoma occurs most commonly in adults between 50 and 70 years of age, although
it has been reported in children as young as 3 years. Renal carcinoma is responsible
for approximately 3% of adult malignancies, and the male to female ratio is 1.5:1.
A strong correlation exists between cigarette smoking and the development of renal
cell carcinoma. Unproven factors that may increase the risk for renal cell carcinoma
include polycystic kidney disease, diabetes mellitus, and chronic dialysis. Up to
85% of renal cell carcinomas are of the clear cell type; 5% to 15% of renal cell carcinomas
are a papillary histologic variant. The main type of treatment for cancer of the kidney
is surgery although radiotherapy may also be recommended. In some people, hormonal
treatment, or biological treatment can be used either after surgery or when a cancer
cannot be removed surgically. Very occasionally, cancer of the kidney will spontaneously
improve without any treatment, but this is rare. Chemotherapy has not yet been shown
to be helpful in treating cancer of the kidney.
3.4 Testicular Cancer
[0032] Testicular cancer primarily affects young men in the 20 to 44 year old age group,
where it is the most common cancer. Overall, testicular cancer is not very common.
Testicular cancer responds particularly well to treatment, and over 9 in 10 patients
are cured. Primary germ cell tumours (GCTs) of the testis, arising by the malignant
transformation, of primordial germ cells, constitute 95 percent testicular neoplasms.
This disease is notable for the young age of the afflicted patients, the totipotent
capacity for differentiation of the tumour cells and its curability; more than 90
percent of all newly diagnosed patients will be cured, and, since the advent of cisplatin-based
chemotherapy about 70 to 80 percent of patients with metastatic disease are cured.
[0033] Surgery, radiotherapy and chemotherapy are the commonly used treatments, depending
on the stage of the cancer and whether is has spread. Chemotherapy is more often used
for non-seminoma testicular cancers, however it is also used for seminoma, which has
spread. Testicular cancer can be treated with different combinations of drugs with
the combination most often used being BEP, Bleomycin, Etoposide and Cisplatin.
3.5 Prostate Cancer
[0034] Cancer of the prostate is the most common malignancy in men in the United States
and the third most common cause of cancer death in men above the age of 55 (after
carcinomas of the lung and colon). Surgery is the most common treatment for early-stage
prostate cancer with radiation therapy being the second. There are also different
forms of hormonal therapy. Prostate cancer cells do not tend to grow rapidly like
some other types of cancer. For this reason traditional chemotherapy drugs have not
proven to be quite as useful as they have been in some of the other major cancers.
Nonetheless, some standard chemotherapies have been shown to be useful - particularly
in late-stage prostate cancer. Although there are three chemotherapy drugs approved
by the U.S. Food and Drug Administration for use in prostate cancer - Taxotere® (docetaxel),
Novantrone® (mitoxantrone hydrochloride) and Emcyt® (estramustine sodium phosphate)
- a number of the most common chemotherapeutics approved for other cancers are used
on an "off-label" basis for late-stage prostrate cancer. Chemotherapy is typically
utilized in patients with advanced stage prostate cancer who are no longer responding
to hormonal therapy. None of these agents are consistently helpful in the disease.
The most common sites of metastases in patients with prostate cancer are the bone
and lymph nodes. The bone metastases are particularly troublesome in that they can
create intense pain for the patient.
3.6 Secondary Bone Cancer
[0035] Secondary bone cancer does not start in the bone, but is the result of cancer cells
spreading to the bone from the primary tumour. Sometimes only one area of bone is
affected, but in other people a number of bone secondaries develop, often in different
bones in the body. Although any type of cancer can spread to the bone, the most common
types are cancers of the breast, prostate, lung, kidney and thyroid. The treatment
for a secondary bone cancer depends on the type of primary cancer. For example, prostate
cancer cells may have broken away from the prostate gland, travelled in the blood
to the bone and begun to grow and multiply there. So the cancer cells in the bone
will respond to the same type of treatment as the cancer cells in the prostate. Although
a secondary bone cancer can occur in any bone in the body, the most commonly affected
bones are those of the spine, ribs, pelvis, skull and the upper bones of the arms
and legs.
3.7 Arsenic and Its Medical Uses
[0036] Arsenic has been used as a pharmaceutical agent for more than 2400 years to treat
a large variety of diseases including cancer, but it is also a poison and carcinogenic
agent. With the rapid evolvement of medicine in the 20th century, the use of medicinal
arsenic waned rapidly. Interest in arsenic compounds revived when it was shown that
daily intravenous administration of arsenic trioxide alone caused complete responses
in a large majority of patients with newly diagnosed and relapsed acute promyelocytic
leukaemia. Additional trials are underway in patients with haematological malignancies
and solid tumours such as prostate and pancreatic cancer. A drawback of arsenic trioxide
is that it is administered intravenously daily in 1-4-hr infusion for up to 6 weeks.
A pilot study with an oral formulation of arsenic trioxide in patients with acute
promyelocytic leukaemia is ongoing. The preliminary results show that the efficacy
and side effects are comparable with intravenous arsenic trioxide. The same was noted
for a pilot study with oral tetra-arsenic tetrasulphide given to patients with acute
promyelocytic leukaemia. Thus, an oral arsenic agent with similar or better efficacy
in leukaemia and solid tumours and fewer side effects, particularly in patients in
whom long term treatment is required, would have costs and quality-of-life benefits.
[0037] Arsenic exists in both trivalent and pentavalent oxidation states as a chemically
unstable sulphide or oxide, or as a salt of sodium, potassium or calcium. Trivalent
arsenicals comprising sodium arsenite and arsenic trioxide inhibit many enzymes by
reacting with biological ligands that possess available sulphur groups. Pentavalent
arsenic is an uncoupler of mitochondrial oxidative phosphorylation. It is thus not
surprising that arsenic trioxide exerts anti-tumour effects by activating apoptosis,
induction of reactive oxygen species, inhibition of angiogenesis and in acute promyelocytic
leukaemia cells also by degradation of PML-RARα fusion protein. The response depends
upon cell type and the form of arsenic.
[0038] In 1991 the National Cancer Institute reported that arsenic trioxide inhibits growth
and promotes apoptosis in many different cancer cell lines and began a research programme
to evaluate its clinical activity in haematologic malignancies, such as acute promyelocytic
leukaemia, acute myeloid leukaemia, acute lymphocytic leukaemia, chronic myelogenous
leukaemia, non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukaemia,
myelodysplastic syndrome, and multiple myeloma. It is also supporting research in
solid tumours, such as advanced hormone-refractory prostate cancer and renal cell
cancer and in cervical cancer and refractory transitional cell carcinoma of the bladder.
[0039] Other clinical studies are underway, including Phase II Studies in Solid Tumours.
Based on promising pre-clinical data, NCI-sponsored clinical trials to examine the
potential of arsenic trioxide for the treatment of solid tumours are under way or
in the final planning stages.
4. Summary of the Invention
[0040] The present invention provides a composition comprising sodium meta-arsenite for
treating metastatic neoplastic disease in a patient. The present invention also provides
the use of sodium meta-arsenite for manufacture of a pharmaceutical composition for
the treatment of metastatic neoplastic disease in a patient.
[0041] The present invention relates to a pharmaceutical composition intended for the treatment
of metastatic urogenital diseases and bone metastasis and to a method of treating
such diseases.
[0042] Accordingly, the present invention provides a pharmaceutical composition intended
for the treatment of metastatic urogenital diseases and bone metastasis in a human,
wherein said pharmaceutical composition contains an effective amount of sodium meta-arsente
(AsO
2Na) and a pharmaceutically acceptable adjuvant.
[0043] The effective amount of arsenous acid alkaline metal salt is 0.0001-1500 mg/kg, preferably
1-1000 mg/kg, more preferably 1-150 mg/kg, and most preferably 50-100 mg/kg of body
weight/day.
[0044] Said pharmaceutical composition preferably occurs in an oral administration form,
wherein said oral administration form is e.g. a tablet, capsule, powder and/or solution
with a pharmaceutically acceptable carrier, diluent or excipient.
[0045] Said urogenital disease comprises essentially cancer of the prostate, bladder, kidney
and testis.
[0046] According to the invention, a chemotherapeutic product comprises of arsenous acid
sodium salt having the formula (I):
[0047] Furthermore, the invention includes pharmaceutical compositions comprising such products
together with a pharmaceutically acceptable carrier or diluent. Suitable carriers
and diluents are well known, as are the principles of formulation of compositions
in unit dosage form and for oral administration.
[0048] The Inventor has explored the potency of three arsenic compounds of different valence
and methylation in panels of human tumour cell lines in vitro, arsenous acid sodium
salt (As
3+), dimethylarsinic acid (As
5+) and arsenic acid (As
5+). Surprisingly arsenous acid sodium salt was the most potent and showed anti-tumour
activity in a human tumour model in vivo, reason to develop arsenous acid sodium salt
further as a novel arsenic compound. Arsenous acid sodium salt surprisingly was more
potent in vitro and showed differential activity in leukaemia, melanoma and mammary
cancer lines than As
2O
3. Arsenous acid sodium salt is surprisingly capable of shortening telomeres of human
cancer cells, inducing cellular senescence and chromosomal abnormalities, but does
not directly inhibit the telomerase activity. The effects indicate that arsenous acid
sodium salt is a telomere inhibitor. Arsenous acid sodium salt was rapidly absorbed
after both i.v. and p.o. administration and remained in the plasma for prolonged periods.
Surprisingly the bioavailability of oral arsenous acid sodium salt was approximately
100%. Animal toxicity studies showed that the main target organs were bone marrow
and lymphoid organs. Thus arsenous acid sodium salt can be administered orally. It
might be used in long-term treatment of cancer patients with solid tumours or leukaemia
at dose levels below the maximum tolerated dose (MTD), alone or in combination with
another treatment modality, maintaining a good quality of life.
[0049] This compound (NaAsO
2) of the present invention has been developed as novel anti-cancer agent. The compound
possesses good cytotoxic activity in a panel of 43 human tumour cell lines in vitro
with an IC50 value of 0.6 µM. Pronounced selectivity was observed in tumour cell lines
derived from leukaemia, mammary cancer and melanoma. In a head-to-head comparison
arsenous acid sodium salt was surprisingly at least 15-fold more potent than the clinically
used agent arsenic trioxide and had also a better differential activity. Arsenous
acid sodium salt combined with 5-fluoruracil (5-FU) or vinblastine may result in additive
effects. Potassium in the arsenite reduced cytotoxic activity.
[0050] In vivo arsenous acid sodium salt (oral and intraperitoneal) was surprisingly borderline
active in 2/7 subcutaneously transplanted human tumour xenografts (renal cell carcinoma
RXF 944LX and mammary cancer MAXF 401). In general the highest efficacy of arsenous
acid sodium salt was obtained with doses of 1/3-2/3 of the maximum tolerated dose
(MTD). The efficacy of the compound was better using daily administrations of 5 or
more days compared with intermittent schedules (every 4 days x3, weekly x 3).
[0051] Surprisingly, oral arsenous acid sodium salt showed a high therapeutic efficacy in
cancer patients suffering from urogenital cancer, mainly prostate and bone metastasis,
following treatment with 2.5, 10, 12.5, 15, 17.5 and 20 mg of arsenous acid sodium
salt capsules for 14 consecutive days.
[0052] Surprisingly the patients all tolerated the arsenous acid sodium salt extremely well
with no adverse events (AE's) or serious adverse events (SAE's) occurring. The study
medication did not cause any disturbance of any patients' well-being feeling. There
was no change during the course of the study in any patients' ECG activity, audiometry
or neurological examinations.
[0053] Surprisingly arsenous acid sodium salt, the compound of invention, has great therapeutic
and safety advantages in comparison to arsenic trioxide. Arsenic trioxide As
2O
3 has been shown to prolong the QT and QT interval corrected for rate (QT
c), which may predispose the patient to potentially fatal aytipical ventricular tachycardia
and produce complete atrioventricular block.
[0054] Further more, adverse events occurring in 10% or more of patients treated with arsenic
trioxide include fatigue, fever, oedema, chest pain, rigors, reactions at the injection
site (ie pain, erythema, oedema), weakness, weight gain, nausea, anorexia, decreased
appetite, diarrhoea or loose stools, vomiting, abdominal pain, dyspepsia, sore throat,
constipation, hypokalemia, hypomagnesemia, increases in serum AST (SGOT) and/or ALT
(SGPT), hyperkalemia, hypocalcemia, headache, insomnia, paresthesia, dizziness, tremor,
cough, dyspnea, epistaxis, hypoxia, pleural effusion, postnasal drip, wheezing, decreased
breath sounds, crepitations, rales, dermatitis, pruritus, ecchymosis, dry skin, erythema,
sweating, tachycardia, ECG abnormalities, sinusitis, herpes simplex, upper respiratory
infection, arthralgia, myalgia, bone pain, back pain, neck pain, limb pain, leukocytosis,
anaemia, thrombocytopenia, neutopenia (may be febrile), hypotension, hypertension,
flushing, pallor, anxiety, depression, ocular irritation, blurred vision and vaginal
haemorrhage.
[0055] Surprisingly none of these adverse events have been observed using the oral arsenous
acid sodium salt, which is the compound of the present invention.
5. Detailed Description of the Invention
[0056] Methods and compositions for the treatment of metastatic urological neoplasm and/or
bone metastasis are described herein.
[0057] The invention is based, in part, on a dosage regime for the oral administration of
a composition comprising of arsenous acid sodium salt. It is also based in part, on
the therapeutic efficacy of the arsenous acid sodium salt of the invention against
certain cancers.
[0058] Also disclosed is a method of treating primary solid tumours in a mammal, which involves
the administration of a non-lethal and therapeutically effective amount of arsenous
acid sodium salt on its own, or in combination with one or more therapeutic agents
to the mammal in need of such therapy.
[0059] Also disclosed is a method for treating disorders of the blood in mammals, which
involves the administration of arsenous acid sodium salt either on its own or in combination
with one or more therapeutic agents into the affected mammal.
[0060] The arsenic compound of the invention, arsenous acid sodium salt, may be utilised
in a variety of known forms for example as a salt, as an organic/inorganic complex,
as an organic chelate or encapsulated in a drug targeting system. In our embodiment,
the arsenous acid sodium salt is prepared in capsules. Generally the skilled artisan
will recognise that the form of arsenous acid sodium salt to be used should be therapeutically
effective without unreasonable toxicity.
[0061] Any suitable route of administration of arsenous acid sodium salt may be used in
accordance with the present invention including for example oral administration, parenteral
administration such as intravenous, subcutaneous, intramuscular and intrathecal and
intranasal, rectal or vaginal administration. Administration may also be made directly
into the tumour or through transdermal patches or implantation devices (particularly
for slow release). Topical administration may also be used.
[0062] The pharmaceutical compositions to be used may be in the form of sterile physiologically
acceptable (aqueous or organic) solutions, colloidal suspensions, creams, ointments,
pastes, capsules, caplets, tablets and cachets. It should also be recognised that
delayed slow or sustained release forms of administration are also included.
[0063] The arsenic compounds of the present invention may be used against a variety of metastatic
neoplastic diseases including, for example, metastatic tumours of the central nervous
system, breast, colon, ovaries, kidneys, lung, liver, bladder, prostate and head and
neck.
5.1 Pharmaceutical Formulation
[0064] Therefore, the present invention relates to a pharmaceutical anti-cancer composition
comprising of a therapeutically effective amount of arsenous acid sodium salt represented
by the following formula (I)
and its pharmaceutically acceptable salts used for the manufacturing of an agent for
the treatment of a cell proliferative disorder and one or more pharmaceutically acceptable
adjuvant, excipient, carrier, buffer, diluent and/or customary pharmaceutical auxiliary.
In a preferred embodiment of the invention the compound of the invention can be administered
in a pharmaceutically acceptable formulation. The present invention pertains to any
pharmaceutically acceptable formulations, such as synthetic or natural polymers in
the form of macromolecular complexes, nanocapsules, microspheres, or beads, and lipid-based
formulations including oil-in-water emulsions, micelles, mixed micelles, synthetic
membrane vesicles, and resealed erythrocytes. In addition to the compound and the
pharmaceutically acceptable polymer, the pharmaceutically acceptable formulation used
in the method of the invention can comprise additional pharmaceutically acceptable
carriers and/or excipients. As used herein, pharmaceutically acceptable carrier includes
any and all solvents, dispersion media, coatings, antibacterial and anti fungal agents,
isotonic and absorption delaying agents, and the like that are physiologically compatible.
For example, the carrier can be suitable for injection into the blood. Excipients
include pharmaceutically acceptable stabilizers and disintegrants. In another embodiment,
the pharmaceutically acceptable formulations comprise lipid-based formulations. Any
of the known lipid-based drug delivery systems can be used in the practice of the
invention. For instance, multi-vesicular liposomes (MVL), multi-lamellar liposomes
(also known as multi-lamellar vesicles or MLV), uni-lamellar liposomes, including
small uni-lamellar liposomes (also known as uni-lamellar vesicles or SUV) and large
uni-lamellar liposomes (also known as large uni-lamellar vesicles or LUV), can all
be used so long as a sustained release rate of the encapsulated compounds can be established.
In one embodiment, the lipid-based formulation can be a multi-vesicular liposome system.
The composition of the synthetic membrane vesicle is usually a combination of phospholipids,
usually in combination with steroids, especially cholcompoundol. Other phospholipids
or other lipids may also be used. Examples of lipids useful in synthetic membrane
vesicle production include phosphatidylglycerols, phosphatidylcholines, phosphatidylserines,
phosphatidylethanolaminos, sphingolipids, cerebrosides, and gangliosides. Preferably
phospholipids including egg phosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine,
dioleoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, and dioleoylphosphatidylglycerol
are used. In another embodiment, the composition containing the compound may be incorporated
or impregnated into a bio-absorbable matrix. In addition, the matrix may be comprised
of the said biopolymer. A suitable biopolymer for the present invention can include
also one or more macromolecules selected from the group consisting of collagen, elastin,
fibronectin, vitronectin, laminin, polyglycolic acid, hyaluronic acid, chondroitin
sulphate, dermatan sulphate, heparin sulphate, heparin, fibrin, cellulose, gelatin,
polylysine, echinonectin, entactin, thrombospondin, uvomorulin, biglycan, decorin;
and dextran. The formulation of these macromolecules into a biopolymer is well known
in the art. In a preferred embodiment, the therapeutic composition is not immunogenic
when administered to a human patient for therapeutic purposes.
[0065] A therapeutic composition of the present invention can include pharmaceutically acceptable
salts of the components therein. Pharmaceutically acceptable salts include the acid
addition salts that are formed with inorganic acids such as, for example, hydrochloric
or phosphoric acids, or such organic acids as acetic, tartaric, mandelic and the like.
Physiologically tolerable carriers are well known in the art. Exemplary of liquid
carriers are sterile aqueous solutions that contain no materials in addition to the
active ingredients and water, or contain a buffer such as sodium phosphate at physiological
pH value, physiological-saline or both, such as phosphate-buffered saline. Still further,
aqueous carriers can contain more than one buffer salt, as well as salts such as sodium
and potassium chlorides, dextrose, propylene glycol, polyethylene glycol and other
solutes. Liquid compositions can also contain liquid phases in addition to and to
the exclusion of water. Exemplary of such additional liquid phases are glycerine,
vegetable oils such as cottonseed oil, organic compounds such as ethyl oleate, and
water-oil emulsions. A therapeutic composition contains a polypeptide of the present
invention, typically an amount of at least 0.1 weight percent of polypeptide per weight
of total therapeutic composition. A weight percent is a ratio by weight of polypeptide
to total composition. Thus, for example, 0.1 weight percent is 0.1 grams of polypeptide
per 100 grams of total composition.
[0066] The term "pharmaceutically acceptable salt" refers to those salts of compounds which
retain the biological effectiveness and properties of the free bases and which are
obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid,
sulphuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic
acid, atoluenesulfonic acid, salicylic acid and the like. The pharmaceutical composition
containing the active ingredient may be in a form suitable for oral use, for example,
as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or
granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended
for oral use may be prepared according to any method known to the art for the manufacture
of pharmaceutical compositions and such compositions may contain one or more agents
selected from the group consisting of sweetening agents, flavouring agents, colouring
agents and preserving agents in order to provide pharmaceutically elegant and palatable
preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically
acceptable excipients, which are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and disintegrating agents, for
example corn starch, or alginic acid; binding agents, for example starch, gelatin
or acacia, and lubricating agents, for example magnesium stearate, stearic acid or
talc. The tablets may be uncoated or they may be coated by known techniques to delay
disintegration and absorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate may be employed. They may also be coated
by the techniques described in the
U.S. Pat. Nos. 4,256,108;
4, 166, 452 ; and
4, 265, 874, to form osmotic therapeutic tablets for control release. A pharmaceutical composition
may also, or alternatively, contain one or more drugs, which may be linked to a modulating
agent or may be free within the composition. Virtually any drug may be administered
in combination with a modulating agent as described herein, for a variety of purposes
as described below. Examples of types of drugs that may be administered with a modulating
agent include analgesics, anaesthetics, antianginals, antifungals, antibiotics, anti-cancer
drugs (e.g., taxol or mitomycin C), antiinflammatories (e.g., ibuprofen and indomethacin),
anthelmintics, antidepressants, antidotes, antiemetics, antihistamines, antihypertensives,
antimalarials, antimicrotubule agents (e.g., colchicine or vinca alkaloids), antimigraine
agents, antimicrobials, antiphsychotics, antipyretics, antiseptics, anti-signalling
agents (e.g., protein kinase C inhibitors or inhibitors of intracellular calcium mobilization),
antiarthritics, antithrombin agents, antituberculotics, antitussives, antivirals,
appetite suppressants, cardioactive drugs, chemical dependency drugs, cathartics,
chemotherapeutic agents, coronary, cerebral or peripheral vasodilators, contraceptive
agents, depressants, diuretics, expectorants, growth factors, hormonal agents, hypnotics,
immunosuppression agents, narcotic antagonists, parasympathomimetics, sedatives, stimulants,
sympathomimetics, toxins (e.g., cholera toxin), tranquillisers and urinary antiinfectives.
[0067] Formulations for oral use may also be presented as hard gelatin capsules where in
the active ingredient is mixed with an inert solid diluent, for example calcium carbonate,
calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient
is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive
oil.
[0068] Aqueous suspensions contain the active materials in a mixture with excipients suitable
for the manufacture of aqueous suspensions. Such excipients are suspending agents,
for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,
sodium alginate polyvinyl-pyrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally occurring phosphatide, for example lecithin, or
condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene
stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols,
for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide
with partial compounds derived from fatty acids and a hexitol such a polyoxyethylene
with partial compounds derived from fatty acids and hexitol anhydrides, for example
polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more
colouring agents, one or more flavouring agents, and one or more sweetening agents,
such as sucrose or saccharin.
[0069] Oily suspensions may be formulated by suspending the active ingredient in a vegetable
oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral
oil such as liquid paraffin. The oily suspensions may contain a thickening agent,
for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those
set forth above, and flavouring agents may be added to provide a palatable oral preparation.
These compositions may be preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0070] Dispersible powders and granules suitable for preparation of an aqueous suspension
by the addition of water provide the active ingredient in admixture with a dispersing
or wetting agent, suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified, for example sweetening, flavouring
and colouring agents, may also be present.
[0071] The pharmaceutical compositions of the invention may also be in the form of oil-in-water
emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis
oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum acacia or gum
tragacanth, naturally-occurring phosphatides, for example soya bean, lecithin, and
compounds or partial compounds derived from fatty acids and hexitol anhydrides, for
example sorbitan monooleate and condensation products of the said partial compounds
with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions
may also contain sweetening and flavouring agents.
[0072] Syrups and elixirs may be formulated with sweetening agents, for example glycerol,
propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent,
a preservative and flavouring and colouring agents. The pharmaceutical compositions
may be in the form of a sterile injectable aqueous or oleagenous suspension. This
suspension may be formulated according to the known art using those suitable dispersing
or wetting agents and suspending agents, which have been mentioned above. The sterile
injectable preparation may also be in a sterile injectable solution or suspension
in a non-toxic parenterally acceptable diluent or solvent, for example as absolution
in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed
are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile,
fixed oils are conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic mono-or diglycerides.
In addition, fatty acids such as oleic acid find use in the preparation of injectables.
[0073] Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of
body weight per day are useful in the treatment of the above-indicated conditions
(about 2.5 mg to about 7 g per patient per day). For example, inflammation may be
effectively treated by the administration of from about 0.01 to 50 mg of the compound
per kilogram of body weight per day (about 0.5 mg to about 3.5 g per patient per day).
The amount of active ingredient that may be combined with the carrier materials to
produce a single dosage form will vary depending upon the host treated and the particular
mode of administration. For example, a formulation intended for the oral administration
of humans may vary from about 5 to about 95% of the total composition. Dosage unit
forms will generally contain between from about 1 mg to about 500 mg of active ingredient.
It will be understood, however, that the specific dose level for any particular patient
will depend upon a variety of factors including the activity of the specific compound
employed, the age, body weight, general health, sex, diet time of administration,
route of administration, rate of excretion, drug combination and the severity of the
particular disease undergoing therapy. The dosage effective amount of compounds according
to the invention will vary depending upon factors including the particular compound,
toxicity, and inhibitory activity, the condition treated, and whether the compound
is administered alone or with other therapies. Typically a dosage effective amount
will range from about 0.0001 mg/kg to 1500 mg/kg, more preferably 1 to 1000 mg/kg,
more preferably from about 1 to 150 mg/kg of body weight, and most preferably about
50 to 100 mg/kg of body weight. The invention relates also to a process or a method
for the treatment of the abovementioned pathological conditions. The compounds of
the present invention can be administered prophylactically or therapeutically, preferably
in an amount that is effective against the mentioned disorders, to a warm-blooded
animal, for example a human, requiring such treatment, the compounds preferably being
used in the form of pharmaceutical compositions.
[0074] Formulation of pharmaceutically-acceptable excipients and carrier solutions is well-known
to those of skill in the art, as is the development of suitable dosing and treatment
regimens for using the particular compositions described herein in a variety of treatment
regimens, including e.g., oral, parenteral, intravenous, intranasal, and intramuscular
administration and formulation.
5.1.1 Oral Delivery
[0075] In certain applications, the pharmaceutical compositions disclosed herein may be
delivered via oral administration to an animal. As such, these compositions may be
formulated with an inert diluent or with an assimilable edible carrier, or they may
be enclosed in hard- or soft-shell gelatin capsule, or they may be compressed into
tablets, or they may be incorporated directly with the food of the diet.
[0076] The active compounds may even be incorporated with excipients and used in the form
of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups,
wafers, and the like. The tablets, troches, pills, capsules and the like may also
contain the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatin;
excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch,
potato starch, alginic acid and the like; a lubricant, such as magnesium stearate;
and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavouring
agent, such as peppermint, oil of wintergreen, or cherry flavouring. When the dosage
unit form is a capsule, it may contain, in addition to materials of the above type,
a liquid carrier. Various other materials may be present as coatings or to otherwise
modify the physical form of the dosage unit. For instance, tablets, pills, or capsules
may be coated with shellac, sugar, or both. Syrup of elixir may contain the active
compound sucrose as a sweetening agent methyl and propylparabens as preservatives,
a dye and flavouring, such as cherry or orange flavour. Of course, any material used
in preparing any dosage unit form should be pharmaceutically pure and substantially
non-toxic in the amounts employed. In addition, the active compounds may be incorporated
into sustained-release preparation and formulations.
[0077] Typically, these formulations may contain at least about 0.1% of the active compound
or more, although the percentage of the active ingredient(s) may, of course, be varied
and may conveniently be between about 1 or 2% and about 60% or 70% or more of the
weight or volume of the total formulation. Naturally, the amount of active compound(s)
in each therapeutically useful composition may be prepared is such a way that a suitable
dosage will be obtained in any given unit dose of the compound. Factors such as solubility,
bioavailability, biological half-life, route of administration, product shelf life,
as well as other pharmacological considerations will be contemplated by one skilled
in the art of preparing such pharmaceutical formulations, and as such, a variety of
dosages and treatment regimens may be desirable.
[0078] For oral administration the compositions of the present invention may alternatively
be incorporated with one or more excipients in the form of a mouthwash, dentifrice,
buccal tablet, oral spray, or sublingual orally administered formulation. For example,
a mouthwash may be prepared incorporating the active ingredient in the required amount
in an appropriate solvent, such as a sodium borate solution (Dobell's Solution). Alternatively,
the active ingredient may be incorporated into an oral solution such as one containing
sodium borate, glycerine and potassium bicarbonate, or dispersed in a dentifrice,
or added in a therapeutically effective amount to a composition that may include water,
binders, abrasives, flavouring agents, foaming agents, and humectants. Alternatively
the compositions may be fashioned into a tablet or solution form that may be placed
under the tongue or otherwise dissolved in the mouth.
5.1.2 Injectable Delivery
[0079] In certain circumstances it will be desirable to deliver the pharmaceutical compositions
disclosed herein parenterally, intravenously, intramuscularly, or even intraperitoneally.
Solutions of the active compounds as freebase or pharmacologically acceptable salts
may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures
thereof and in oils. Under ordinary conditions of storage and use, these preparations
contain a preservative to prevent the growth of microorganisms.
[0080] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions
or dispersions and sterile powders for the extemporaneous preparation of sterile injectable
solutions or dispersions. In all cases the form must be sterile and must be fluid
to the extent that easy syringability exists. It must be stable under the conditions
of manufacture and storage and must be preserved against the contaminating action
of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene
glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof,
and/or vegetable oils. Proper fluidity may be maintained, for example, by the use
of a coating, such as lecithin, by the maintenance of the required particle size in
the case of dispersion and by the use of surfactants. The prevention of the action
of microorganisms can be facilitated by various antibacterial and antifungal agents,
for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
In many cases, it will be preferable to include isotonic agents, for example, sugars
or sodium chloride. Prolonged absorption of the injectable compositions can be brought
about by the use in the compositions of agents delaying absorption, for example, aluminium
monostearate and gelatin.
[0081] For parenteral administration in an aqueous solution, for example, the solution should
be suitably buffered if necessary and the liquid diluent first rendered isotonic with
sufficient saline or glucose. These particular aqueous solutions are especially suitable
for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In
this connection, a sterile aqueous medium that can be employed will be known to those
of skill in the art in light of the present disclosure. For example, one dosage may
be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis
fluid or injected at the proposed site of infusion. Some variation in dosage will
necessarily occur depending on the condition of the subject being treated. The person
responsible for administration will, in any event, determine the appropriate dose
for the individual subject. Moreover, for human administration, preparations should
meet sterility, pyrogenicity, and the general safety and purity standards as required
by national or regional offices of biologics standards.
[0082] Sterile injectable solutions are prepared by incorporating the active compounds in
the required amount in the appropriate solvent with several of the other ingredients
enumerated above, as required, followed by filtered sterilization. Generally, dispersions
are prepared by incorporating the various sterilized active ingredients into a sterile
vehicle which contains the basic dispersion medium and the required other ingredients
from those enumerated above. In the case of sterile powders for the preparation of
sterile injectable solutions, the preferred methods of preparation are vacuum-drying
and freeze-drying techniques which yield a powder of the active ingredient plus any
additional desired ingredient from a previously sterile-filtered solution thereof.
[0083] The compositions disclosed herein may be formulated in a neutral or salt form. Pharmaceutically-acceptable
salts, include the acid addition salts (formed with the free amino groups of the protein)
and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric
acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
Salts formed with the free carboxyl groups can also be derived from inorganic bases
such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides,
and such organic bases as isopropylamine, trimethylamine, histidine, procaine and
the like. Upon formulation, solutions will be administered in a manner compatible
with the dosage formulation and in such amount as is therapeutically effective. The
formulations are easily administered in a variety of dosage forms such as injectable
solutions, drug-release capsules, and the like.
[0084] As used herein, "carrier" includes any and all solvents, dispersion media, vehicles,
coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying
agents, buffers, carrier solutions, suspensions, colloids, and the like. The use of
such media and agents for pharmaceutical active substances is well known in the art.
Except insofar as any conventional media or agent is incompatible with the active
ingredient, its use in the therapeutic compositions is contemplated. Supplementary
active ingredients can also be incorporated into the compositions.
[0085] The phrase "pharmaceutically-acceptable" refers to molecular entities and compositions
that do not produce an allergic or similar untoward reaction when administered to
a human. The preparation of an aqueous composition that contains a protein as an active
ingredient is well understood in the art. Typically, such compositions are prepared
as injectables, either as liquid solutions or suspensions; solid forms suitable for
solution in, or suspension in, liquid prior to injection can also be prepared. The
preparation can also be emulsified.
5.1.3 Nasal Delivery
[0086] In certain embodiments, intranasal sprays, inhalation, and/or other aerosol delivery
vehicles may deliver the pharmaceutical compositions. Likewise, the delivery of drugs
using intranasal microparticle resins and lysophosphatidyl-glycerol compounds are
also well known in the pharmaceutical arts.
5.2 Target cancers
[0087] The subjects treated will typically comprise of mammals and most preferably will
be human subjects e.g. human cancer subjects. The compounds of the invention may be
used alone or in combination. Additionally the treated compounds may be utilised with
other types of treatments. For example, the subject compounds may be used with other
chemotherapies e.g. tamoxifen, taxol, methothrexate, biologicals such as antibodies,
growth factors or lymphokines, radiation etc. Combination therapies may result in
synergistic results. The preferred indication is cancer especially the cancers identified
previously.
[0088] The compositions and methods provided herein are particularly deemed useful for the
treatment of metastatic neoplastic tumours including solid tumours such as breast,
central nervous system, colon, ovarian, kidney, lung, liver, bladder, prostate, head
and neck etc. More specifically, tumours, which may be treated by the compositions
and methods of the invention, include tumours of an epithelial origin such as, but
not limited to:
Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated
large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,
sarcoma, lymphoma, chondromatous hamartoma, mesotheliorna; Gastrointestinal: oesophagus
(squamous cell carcinoma, adenocarcinoma), gastric carcinoma, colorectal carcinoma;
Urogenital tract: kidney (adenocarcinoma, Wilm's tumour [nephroblastoma], lymphoma,
leukaemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma,
adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma); Liver: hepatoma
(hepatocellular carcinoma); Bone: osteogenic sarcoma (Osteosarcoma); Nervous system:
neuroblastoma, Retinoblastoma, Glioblastoma, Oligodendroglioma; Gynaecological: cervix
(cervical carcinomas, pre-tumour cervical dysplasia); Haematologic: blood (myeloid
leukaemia [acute and chronic], acute lymphoblastic leukaemia, chronic lymphocytic
leukaemia), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin:
malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma
and Glands and ducts: adenocarcinoma, papillary carcinoma and papillary adenocarcinoma.
Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any
one of the above-identified conditions.
[0089] The term "leukaemia" refers broadly to progressive, malignant diseases of the blood-forming
organs and is generally characterized by a distorted proliferation and development
of leukocytes and their precursors in the blood and bone marrow. Leukaemia is generally
clinically classified on the basis of (1) the duration and character. of the disease-acute
or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous),
or monocytic and (3) the increase or non-increase in the number abnormal cells in
the blood-leukaemia or aleukaemic (subleukaemic). The P388 leukaemia model is widely
accepted as being predictive of in vivo anti-leukaemic activity. It is believed that
compound that tests positive in the P388 assay will generally exhibit some level of
anti-leukaemic activity in vivo regardless of the type of leukaemia being treated.
Accordingly, the present invention includes a method of treating leukaemia, and, preferably,
a method of treating acute nonlymphocytic leukaemia, chronic lymphocytic leukaemia,
acute granulocytic leukaemia, chronic granulocytic leukaemia, acute promyelocytic
leukaemia, adult T-cell leukaemia, aleukaemic leukaemia, a leukocythemic leukaemia,
basophylic leukaemia, blast cell leukaemia, bovine leukaemia, chronic myelocytic leukaemia,
leukaemia cutis, embryonal leukaemia, eosinophilic leukaemia, Gross' leukaemia, hairy-cell
leukaemia, hemoblastic leukaemia, hemocytoblastic leukaemia, histiocytic leukaemia,
stem cell leukaemia, acute monocytic leukaemia, leukopenic leukaemia, lymphatic leukaemia,
lymphoblastic leukaemia, lymphocytic leukaemia, lymphogenous leukaemia, lymphoid leukaemia,
lymphosarcoma cell leukaemia, mast cell leukaemia, megakaryocytic leukaemia, micromyeloblastic
leukaemia, monocytic leukaemia, myeloblastic leukaemia, myelocytic leukaemia, myeloid
granulocytic leukaemia, myelomonocytic leukaemia, Naegeli leukaemia, plasma cell leukaemia,
plasmacytic leukaemia, promyelocytic leukaemia, Rieder cell leukaemia, Schilling's
leukaemia, stem cell leukaemia, subleukaemic leukaemia, and undifferentiated cell
leukaemia.
[0090] The term "sarcoma" generally refers to a tumour which is made up of a substance like
the embryonic connective tissue and is generally composed of closely packed cells
embedded in a fibrillar or homogeneous substance. Sarcomas which can be treated with
compound of the invention and optionally a potentiator and/or chemotherapeutic agent
include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma,
osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part
sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma,
embryonal sarcoma, Wilms' tumour sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's
sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma,
Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic
sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma,
Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma
sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma,
synovial sarcoma, and telangiectaltic sarcoma.
[0091] The term "melanoma" is taken to mean a tumour arising from the melanocytic system
of the skin and other organs. Melanomas which can be treated with said compounds and
optionally a potentiator and/or another chemotherapeutic agent include, for example,
acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's
melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna
melanoma, malignant melanoma, nodular melanoma, subungal melanoma, and superficial
spreading melanoma.
[0092] The term "carcinoma" refers to a malignant new growth made up of epithelial cells
tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary
carcinomas which can be treated with said compound and optionally a potentiator and/or
a chemotherapeutic agent include, for example, acinar carcinoma, acinous carcinoma,
adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma
of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma,
carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar
carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular
carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma,
cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma,
cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma,
encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic
carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous
carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma,
granulosa cell carcinoma, hair-matrix carcinoma, haematoid carcinoma, hepatocellular
carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile
embryonal carcinoma, carcinoma in situ, infraepidermal carcinoma, intraepithelial
carcinoma, Krorapecher ' s carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma,
lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial
carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma
molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid
carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal
carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary
carcinoma, periportal carcinoma, pre-invasive carcinoma, prickle cell carcinoma, pultaceous
carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes,
schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma,
carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma,
spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma,
string carcinoma , carcinoma telangiectaticum, carcinoma telangiectodes, transitional
cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and
carcinoma villosum.
[0093] Additional cancers which can be treated with compound according to the invention
include, for example, Hodgkin s Disease, Non-Hodgkin's Lymphoma, multiple myeloma,
neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, small-cell
lung tumours, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant
carcinoid, unary bladder cancer, testicular cancer, lymphomas, thyroid cancer, neuroblastoma,
esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer,
endometrial cancer, adrenal cortical cancer, and prostate cancer.
[0094] The present invention provides compositions for use in enhancing tumour specific
immunity in individuals suffering from colorectal cancer metastasised to the liver,
in order to inhibit the progression of the neoplastic disease. Preferred methods of
treating these neoplastic diseases comprise administering a composition of arsenic,
which elicits an immune response against tumour cells.
[0095] The present invention provides compositions for use in enhancing specific immunity
in individuals suffering from hepatocellular carcinoma in order to inhibit the progression
of the neoplastic disease and ultimately irradiate all preneoplastic and neoplastic
cells.
[0096] Also disclosed are hsp compositions and methods for enhancing specific immunity to
preneoplastic and neoplastic mammary cells in women. The present invention also provides
compositions and methods for inhibiting cancer cell proliferation and metastasis.
These compositions can be applied alone or in combination with each other or with
biological response modifiers.
6. Working examples
[0097] The following subsections describe the testing of a pharmaceutical composition comprising
arsenous acid sodium salt in vivo using cancer patients. The results demonstrate that
arsenous acid sodium salt administered orally is effective in the treatment of urogenital
cancer.
6.1 Methods and materials
[0098] Cancer patients suffering from prostate and/or urogenital cancer have been treated
in an ICH-GCP clinical study with oral arsenous acid sodium salt. The patients were
suffering from urogenital cancer, mainly prostate cancer and bone metastasis, not
amenable to any established methods of therapy and were treated with arsenous acid
sodium salt over 7 different dosing levels. Arsenous acid sodium salt is thought to
act as a telomere poison as it is capable of shortening the telomeres of human cancer
cells, which leads to chromosomal abnormalities but doesn't inhibit telomerase activity.
[0099] Arsenous acid sodium salt was taken daily for 14 consecutive days according to the
dose level treatment scheme below:
- Treatment Level 1:
- One capsule each 2.5 mg sodium meta-arsenite daily (every 24 hours) Prior to breakfast
- Treatment Level 2:
- Two capsules each 2.5 mg arsenous acid sodium salt daily 1 prior to breakfast, 1 prior
to dinner
- Treatment Level 3 :
- Four capsules each 2.5 mg arsenous acid sodium salt daily 1 prior to breakfast, 2 prior
to lunch, 1 prior to dinner
- Treatment Level 4:
- Five capsules each 2.5 mg arsenous acid sodium salt daily
2 prior to breakfast, 2 prior to lunch, 1 prior to dinner
- Treatment Level 5:
- Six capsules each 2.5 mg arsenous acid sodium salt daily
2 prior to breakfast, 2 prior to lunch, 2 prior to dinner
[0100] Patient visits were planned for the control of the compliance, toxicity and safety
and were held as follows:
- Visit 1:
- was held between day -7 and day 0 (start of treatment)
- Visit 2:
- on the first day of treatment with sodium meta-arsenite
- Visit 3:
- on day 8 of treatment with arsenous acid sodium salt
- Visit 4:
- on day 15 (approx. 24 hours) after the completion of 14 consecutive days of treatment
with arsenous acid sodium salt
- Visit 5:
- on day 22 (approx. 7 days after the completion of 14 consecutive days of treatment
with arsenous acid sodium salt
- Visit 6:
- on day 42 (approx. 28 days) after the completion of the 14 days consecutive days of
treatment with arsenous acid sodium salt
[0101] The following target parameters were assessed during this study: toxicity profile,
efficacy, liver enzyme parameters (GOT, GPT, α-GT, AP), kidney function, haematology
functions, tumour marker evaluations (CEA and PSA) and the pharmacokinetics of arsenous
acid sodium salt.
6.2 Results
[0102] Below is a summary of the clinical findings for each patient involved in this study.
The findings reported include the values for the tumour markers CEA (carcinoembryonal
antigen) and PSA (prostate specific antigen) and results for efficacy, toxicity and
safety.
Table 1 and 2 presents the summary of patient details with PSA and CEA values:
[0103]
[0104] Suprisingly, the patients all tolerated the arsenous acid sodium salt extremely well.
No adverse events (AE' s) or serious adverse events (SAE' s) occurred. The study medication
did not cause any disturbance of any patient's well-being feeling. There was no change
during the course of the study in any patient's ECG activity, audiometry or neurological
examinations None of the patients had radiotherapy prior to treatment with arsenous
acid sodium salt. The arsenous acid sodium salt showed a high level of efficacy.
6.2.1 Example 1 : Patient K.F.
[0105] Histology: Advanced, inoperable, solid prostate cancer with infiltration of the rectal mucosal
wall, 11.02.2004
[0106] Stage: Dukes C, pT 4 Gleason score 6 Therapy
[0107] Since the patient suffers from a coronary heart disease with a myocardial infarction
and implantation of coronary stents, a radical prostatovesiculectomy could not be
performed and a full androgen ablation with a LHRH antagonist (one profact s.c injection
every 3 months) and an oral antiandrogen (androcur tablets dosage 1x1/d after lunch)
was initiated. A palliative transurethral resection of the prostate (TURP) to ameliorate
micturition was performed in May 2004.
[0108] This patient took part in the dose levels 1, 3 and 5 of the arsenous acid sodium
salt study The results for this patient indicate a clinically significant change in
PSA levels for all 3 drug dose levels. Dose level one (2.5mg arsenous acid sodium
salt) indicated a significant decrease in PSA from 0.29 ng/ml to 0.16 ng/ml. This
decrease corresponds to a reduction in tumour activity of 44.83%. Dose level three
(10mg arsenous acid sodium salt) indicate an increase of PSA from 0.16 to 0.18 ng/ml.
Dose level five (12.5mg arsenous acid sodium salt) again indicates an increase, this
time from 0.17 to 0.18 ng/ml. Neither dose level 3 or 5 showed any significant change
in tumour activity.
[0109] Dose level one showed a decrease in tumour size from 20x35mm to 20x34mm. Dose level
three also showed a decrease from 20x35 to 20x34mm while dose level five showed no
change in size from 20x34mm.
[0110] The secondary parameters (safety parameters) showed no clinically significant results
at any of the dose levels. A reversible increase in liver transaminases sGPT and sGOT
was observed during the intake of arsenous acid sodium salt in dose group III and
V (visit 3 and 4). In visit 5 the transaminases almost returned to normal values.
This increase seems to be related to the administration of the investigative drug
arsenous acid sodium salt.
[0111] The evaluation/judgement of clinical response/progression for dose level one was that
of a partial response. For both dose levels three and five, the disease showed stability.
6.2.2 Example 2 : Patient G.R.
[0112] Histology: Advanced, inoperable, solid prostate cancer with an extraglandular tumour growth
[0113] Stage: Dukes C, pT 4 Gleason score 4
Therapy
[0114] As well as suffering from a prostate carcinoma, this patient also suffered from a
renal cell carcinoma (since cured by radical nephrectomy) and a superficial bladder
cancer (no tumour recurrence). The patient was included in the study due the continued
rising of PSA levels after a complete androgen ablation with a LHRH antagonist (one
profact s.c injection every 3 months) and an oral antiandrogen (casodex tablets dosage
1x1/d after lunch).
[0115] This patient took part in the dose levels 1, 3 and 5 of the arsenous acid sodium
salt study. The results for this patient indicate a clinically significant change
in PSA levels for all 3 arsenous acid sodium salt dose levels. Dose level one indicated
a significant decrease in PSA from 1.61 ng/ml to 0.37 ng/ml. This decrease corresponds
to a reduction in tumour activity of 77.1%. Dose levels three and five indicate a
decrease of PSA from 0.37 to 0.12 ng/ml and 0.11 to 0.07 ng/ml respectively. Dose
level three showed a reduction in tumour activity of a further 67.56%, while dose
level five showed no significant change.
[0116] Dose level one showed a decrease in tumour size from 12.5x65mm to 0.8x30mm. Dose
level three also showed a decrease in the prostate tumour from 60x25 to 50x25mm while
dose level five showed no change in size.
[0117] The secondary parameters (safety parameters) showed no clinically significant results
at any of the dose levels. Pre-study elevated triglycerides and cholesterol level
had been detected which were unchanged during the course of the study. Glucose levels
always appeared elevated which could be explained by alimentary reasons since blood
probes were always taken in the morning after an opulent breakfast.
[0118] The evaluation/judgement of clinical response/progression for all three dose levels
was that of a partial response.
6.2.3 Example 3 : Patient E.S.
[0119] Histology: Advanced, inoperable, solid, androgen resistant prostate cancer with an extra-capsular
tumour growth.
[0120] Stage: Dukes C, pT 4 Gleason score 4
Therapy
[0121] As well as suffering from a prostate carcinoma, this patient also suffers from rectum
cancer. This patient was included because of the advanced and inoperable situation.
An androgen ablation with a LHRH antagonist (one profact s.c injection every 3 months)
has been performed.
[0122] This patient took part in the dose levels 1, 3 and 5 of the arsenous acid sodium
salt study. The results for this patient indicate a clinically significant change
in PSA levels for all 3 drug dose levels. Dose levels one and three indicate a decrease
of PSA from 0.24 ng/ml to 0.11 ng/ml and 0.11 to 0.08 ng/ml respectively. Dose level
five showed no change from 0.09 ng/ml. Dose level one showed a reduction in tumour
activity of 54.12% and level three, a further 67.56%. Dose level five showed no significant
change.
[0123] Dose level one showed a decrease in tumour size from 30x35mm to 30x30mm. Dose levels
three and five showed no change in size.
[0124] The secondary parameters (safety parameters) showed no clinically significant results
at any of the dose levels. A reversible, and slight increase in sGPT was detected.
[0125] The evaluation/judgement of clinical response/progression for dose levels one and
three was that of a partial response. Dose level five showed disease stability.
6.2.4 Example 4: Patient J.S.
[0126] Histology: Advanced, inoperable, androgen-resistant solid prostate cancer with an extra-glandular
tumour growth.
[0127] Stage: Dukes C, pT 4 Gleason score 8
Therapy
[0128] The patient was included in the study due the continued rising of PSA levels after
subcapsular orchiectomy for androgen ablation.
[0129] This patient took part in the dose levels 1, 3 and 5 of the arsenous acid sodium
salt study. The results for this patient indicate a clinically significant change
in PSA levels for all 3 drug dose levels. Dose level one indicated an increase in
PSA from 0.19 ng/ml to 0.21 ng/ml. Dose levels three and five indicate an increase
of PSA from 0.21 ng/ml to 0.27 ng/ml and a decrease of PSA from 0.27 to 0.24 ng/ml
respectively. Dose levels one and three showed an increase in tumour progression while
dose level five showed no significant change.
[0130] Dose level one showed an increase in tumour size from 30x30mm to 35x35mm. Dose levels
three and five showed no change from 30x35mm.
[0131] The secondary parameters (safety parameters) showed no clinically significant results
at any of the dose levels. A pre-study existing elevation of sGGT and thrombocytosis
remained unchanged during the course of the study.
[0132] The evaluation/judgement of clinical response/progression for dose levels one and
three was that of progression of disease. Dose level five showed a partial response
to the arsenous acid sodium salt.
6.2.5 Example 5: Patient D.B.
[0133] Histology: Local recurrence of a solid prostate cancer after radical prostatectomy (stage pT2C
Gleason 6) with bladder neck infiltration, inoperable.
[0134] Stage: Dukes C, pT 4 Gleason score 6
Therapy
[0135] This patient was included in the study due the continued rising of PSA levels after
radical prostatectomy and complete androgen ablation with a LHRH antagonist (one profact
s.c injection every 3 months) and an oral antiandrogen (casodex tablets dosage 1x1/d
after lunch).
[0136] This patient took part in the dose levels 1, 3 and 5 of the arsenous acid sodium
salt study. The results for this patient indicate a clinically significant change
in PSA levels for drug dose levels one. Dose level one indicated a significant decrease
in PSA from 0.45 ng/ml to 0.04 ng/ml. This decrease corresponds to a reduction in
tumour activity of 91.11%. Dose levels three and five showed no change from 0.04 ng/ml.
[0137] The measurement of tumour lesions was not obtainable by any of the standard measuring
means.
[0138] The secondary parameters (safety parameters) showed no clinically significant results
at any of the dose levels. A reversible increase of liver transaminases sGOT, sGPT
and sGGT was observed.
[0139] The evaluation/judgement of clinical response/progression for dose level one was that
of a partial response. For both dose levels three and five, the disease showed a complete
response to the arsenous acid sodium salt.
6.2.6 Example 6: Patient H-W.S.
[0140] Histology: Advanced, inoperable, solid prostate cancer with an extraglandular tumour growth
in the bladder neck and pelvic wall and a dissemination of bone metastases.
[0141] Stage: Dukes C, pT 4 Gleason score 9 M2
Therapy
[0142] The patient was included in the study because of the advanced status of the detected
prostate cancer with multiple bone metastases invading the whole skeleton. A complete
androgen ablation with a LHRH antagonist (one profact s.c injection every 3 months)
and an oral antiandrogen (casodex tablets dosage 1x1/d after lunch) was performed.
[0143] This patient took part in the dose levels 2 and 4 of the arsenous acid sodium salt
study. The results for this patient indicate a clinically significant change in PSA
levels for both drug dose levels. Dose level two indicated a decrease in PSA from
725 ng/ml to 6.15 ng/ml with a decrease in tumour activity of 99.15%, while dose level
four indicated a decrease of PSA from 6.15 ng/ml to 3.67 ng/ml with a further tumour
activity reduction of 40.32%. Dose level two showed a decrease in tumour size from
65x40mm to 15x30mm while dose level four showed no change in size from15x40mm.
[0144] The secondary parameters (safety parameters) showed no clinically significant results
at any of the dose levels. The patients' quality of life was strongly ameliorated
by arsenous acid sodium salt. A pre-study elevation of sGGT due to alcohol consumption
worsened during the course of the study. The hemoglobin concentration increased from
10.0 to 11.1 g/l whereas the PSA decreased from 725 to 3.67 ng/ml.
[0145] The evaluation/judgement of clinical response/progression for both dose levels was
that of a partial response to the arsenous acid sodium salt.
6.3 Conclusion
[0146] Overall those patients taking part in dose levels 1, 3 and 5 showed, for the most
part, a reduction in their PSA levels and tumour size. Most patients showed
at least a partial response to the arsenous acid sodium salt with one patient showing a stable
disease status. The- patient in dose levels 2 and 4, H-W.S., showed a very clear response
to the arsenous acid sodium salt treatment with PSA levels decreasing dramatically
(99.15% reduction in tumour activity) as well as a considerable decrease in tumour
size. The safety (laboratory) parameters showed no clinically significant results.
The arsenous acid sodium salt was surprisingly very well tolerated with no AE's or
SAE'S occurring. Overall the oral arsenous acid sodium salt, even at low doses and
for relatively short treatment periods, showed a surprisingly very positive response
for the treatment of prostate and/or urogenital cancer and bone metastasis.